The therapy of chronic lymphocytic leukemia (CLL) has changed significantly in the past decade with the introduction of fludarabine and new monoclonal antibody therapies. Similarly, our ability to predict which patients will have rapid progression following diagnosis has been greatly enhanced by the identification of new genetic and molecular markers of the disease. The impact of different types of chemoimmunotherapy on these specific subtypes of CLL has not been adequately studied to date, although our preliminary data suggest that alemtuzumab may be effective against resistant clones of CLL. This proposal seeks to study the influence select biologic markers have on outcome with respect to complete remission, progression-free survival and overall survival from two cooperative group studies CALGB 9712 and CALGB 10101 employing two types of chemoimmunotherapy. Our aims include: 1) to determine the significance of IgVH mutational status with respect to treatment outcome following receipt of two different chemoimmunotherapies and the association of IgVH mutational status with other high risk genetic features and surrogate markers including ZAP-70, dysfunctional p53 and high risk interphase abnormalities; and 2) to determine the significance of p53 dysfunction in CLL with respect to treatment outcome and to validate surrogate markers for detecting mutations of p53 and ATM. These studies together with later larger planned prospective studies will allow us to identify select poor prognosis features associated with poor therapy outcome in selective subsets of CLL patients to facilitate risk adapted therapy. Such therapy would potentially administer different types of chemoimmunotherapy based upon the presence or absence of IgVH mutational status and p53 dysfunction.